NM_000321.3:c.607+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000321.3(RB1):​c.607+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

RB1
NM_000321.3 splice_donor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.00
Variant links:
Genes affected
RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-48349024-G-A is Pathogenic according to our data. Variant chr13-48349024-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 419970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RB1NM_000321.3 linkc.607+1G>A splice_donor_variant, intron_variant Intron 6 of 26 ENST00000267163.6 NP_000312.2 P06400A0A024RDV3
RB1NM_001407165.1 linkc.607+1G>A splice_donor_variant, intron_variant Intron 6 of 26 NP_001394094.1
RB1NM_001407166.1 linkc.607+1G>A splice_donor_variant, intron_variant Intron 6 of 16 NP_001394095.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RB1ENST00000267163.6 linkc.607+1G>A splice_donor_variant, intron_variant Intron 6 of 26 1 NM_000321.3 ENSP00000267163.4 P06400
RB1ENST00000467505.5 linkn.138-10993G>A intron_variant Intron 1 of 2 1 ENSP00000434702.1 Q92728
RB1ENST00000650461.1 linkc.607+1G>A splice_donor_variant, intron_variant Intron 6 of 26 ENSP00000497193.1 A0A3B3IS71
RB1ENST00000525036.1 linkn.769+1G>A splice_donor_variant, intron_variant Intron 6 of 6 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinoblastoma Pathogenic:3
May 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects a donor splice site in intron 6 of the RB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with retinoblastoma (PMID: 7795591, 34277001). In at least one individual the variant was observed to be de novo. This variant is also known as intron 6+1G>A. ClinVar contains an entry for this variant (Variation ID: 419970). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 05, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 20, 2024
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Case and Pedigree Information: BILATERAL CASES:9, UNILATERAL CASES:0, TOTAL CASES:9, PEDIGREES:9. ACMG Codes Applied:PVS1, PM2, PS4SUP -

not provided Pathogenic:2
May 08, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as g.45867G>A; This variant is associated with the following publications: (PMID: 25525159, 7795591, 14722923, 8776589, 12541220, 16343894, 17096365, 33493472, 34277001) -

Feb 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1
Oct 25, 2016
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.607+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the RB1 gene. This pathogenic mutation has been reported in numerous individuals with bilateral retinoblastoma (Blanquet V et al. Hum. Mol. Genet. 1995 Mar;4:383-8; Houdayer C et al. Hum. Mutat. 2004 Feb;23:193-202; Nichols KE et al. Hum. Mutat. 2005 Jun;25:566-74; Brichard B et al. Eur. J. Cancer 2006 Jan;42:65-72). Of note, this alteration is also referred to as 745+1G>A and g.45867G>A in the literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Lynch syndrome 4 Pathogenic:1
Sep 27, 2018
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
33
DANN
Uncertain
0.98
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Uncertain
0.81
D
GERP RS
4.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.97
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776789; hg19: chr13-48923160; COSMIC: COSV57310480; API